Graphical Abstract:

Abstract:

Background & Objective: Helicobacter pylori infection is one of the primary causes of peptic
ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug
resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against
H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant
role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has
been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial
IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural
and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial
enzyme selectively.

Methods: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl
indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined
for their inhibitory potential against recombinant HpIMPDH.

Results: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database
with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively.

Conclusion: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only
four-fold less potent and can be a good lead for further development of selective and potent inhibitors of
HpIMPDH.

Background & Objective: Helicobacter pylori infection is one of the primary causes of peptic
ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug
resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against
H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant
role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has
been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial
IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural
and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial
enzyme selectively.

Methods: In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl
indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined
for their inhibitory potential against recombinant HpIMPDH.

Results: In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database
with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively.

Conclusion: When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only
four-fold less potent and can be a good lead for further development of selective and potent inhibitors of
HpIMPDH.